Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[N:2]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+:3]=[N-:4].[CH3:11][Si:12]([CH3:22])([CH3:21])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[Cl-].[NH4+]>C(O)C>[N:2]([C:5](=[CH:17][C:16]1[CH:19]=[CH:20][C:13]([Si:12]([CH3:11])([CH3:22])[CH3:21])=[CH:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+:3]=[N-:4]
Reactant: C[Si](C)(C)c1ccc(C=O)cc1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=Cc1ccc([Si](C)(C)C)cc1)N=[N+]=[N-]
Temperature: 25 °C
Yield: 62.4 %

Procedure:
1.26 g (54.96 mmol) of sodium and 30 mL of anhydrous ethanol are introduced into a 100 mL round-bottomed flask, equipped with a magnetic stirrer and maintained under a nitrogen atmosphere. The reaction mixture is stirred at room temperature until a homogeneous solution is obtained. To this solution, cooled to −10° C., is added dropwise a solution containing 16.83 mL (54.96 mmol) of ethyl azidoacetate (34% in CH2Cl2) and 5 g (27.48 mmol) of 4-trimethylsilylbenzaldehyde in 5 mL of ethanol. The reaction mixture is then stirred at 0° C. for 4 hours. The reaction medium is hydrolysed by adding, with vigorous stirring, 100 mL of ammonium chloride solution (30% aqueous). The product is extracted with three times 50 mL of ethyl acetate. The combined organic phases are washed with twice 20 mL of water, dried over sodium sulfate and concentrated under reduced pressure. The resulting oil is purified by chromatography on a column of silica gel, eluting with a mixture of heptane and dichloromethane. 4.96 g of the expected product are isolated in the form of a yellow oil.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.[N-:10]=[N+:11]=[N-:12].[Na+].Cl>CN(C=O)C>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:12][N:11]=[N:10][N:8]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nnn[nH]2)cc1
Temperature: 135 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
A solution of 10.0 grams (0.085 mole) of para-toluonitrile in 160 mL of DMF was stirred and 5.6 grams (0.085 mole) of sodium azide was added. Upon completion of addition, the reaction mixture was warmed to 135° C. where it stirred for three hours. The reaction mixture was then cooled and poured into 200 mL of stirred, cold aqueous 1N hydrochloric acid. Upon completion of addition, the mixture was stirred for five minutes and filtered to collect a white solid. The solid was dried for 16 hours in a vacuum oven at 35–40° C., yielding 7.1 grams of the subject compound. The reaction was repeated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].CC(O)=[O:13].O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:13])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(C)ccc1Cl
Reactant: CC(=O)O
Solvent: O
Product: COc1cc(C=O)ccc1Cl
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Ceric ammonium nitrate (43.3 g, 79.0 mmol, 4.00 equiv) was dissolved in 1:1 HOAc/H2O (200 mL). This solution was added dropwise over one hour to a stirred solution of the product from Step 1 (3.09 g, 19.7 mmol, 1.00 equiv) in 1:1 HOAc/H2O (100 mL) at 100° C. After the addition was complete, the reaction was stirred for an additional 15 minutes. The reaction was cooled, diluted with H2O and extracted twice with Et2O. The combined organic extracts were washed three times with H2O, three times with satd. NaHCO3, and once with brine. The organic phase was dried over MgSO4 and concentrated en vacuo to afford the title compound (3.00 g, 89%) as an amber oil. 1H NMR (400 MHz, CDCL3) 9.97 (s, 1H), 7.57 (d, 1H), 7.46 (s, 1H), 7.43 (d, 1H), 4.00 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)=[CH:10]3)[C:6]=2[CH:21]=1.[C:22]([N:26]1[CH2:31][CH2:30][CH:29]([SH:32])[CH2:28][CH2:27]1)([CH3:25])([CH3:24])[CH3:23].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:22]([N:26]1[CH2:31][CH2:30][CH:29]([S:32][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[CH:10]=[C:9]([C:15]5[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=5)[N:8]=[C:7]4[C:6]=3[CH:21]=2)[CH2:28][CH2:27]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Brc1ccc2c(c1)-c1nc(-c3cccnc3)cn1CCO2
Reactant: CC(C)(C)N1CCC(S)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4cccnc4)cn2CCO3)CC1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of 9-bromo-2-pyridin-3-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (35 mg, 0.10 mmol), 1-tert-butylpiperidine-4-thiol (53 mg, 0.30 mmol), Pd2(dba)3 (9 mg, 10 mol %), XantPhos (12 mg, 20 mol %) and DIPEA (72 μL, 0.41 mmol) in dioxane (2 mL) was purged with argon and heated at 120° C. for 40 min, then 130° C. for 1 h and 140° C. for 1 h using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-20% 2M NH3/MeOH in EtOAc then C18, gradient 2-20% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 153 as an off-white solid (6 mg, 15%). LCMS: RT 2.42 min [M+H]+ 435.1. 1H NMR (CDCl3, 400 MHz): δ 9.03-9.02 (1H, m), 8.75-8.72 (1H, m), 8.51 (1H, dd, J=4.82, 1.67 Hz), 8.21 (1H, d, J=7.88 Hz), 7.35-7.33 (3H, m), 6.99 (1H, d, J=8.26 Hz), 4.52-4.50 (2H, m), 4.46-4.44 (2H, m), 3.03-2.98 (2H, br m), 2.20 (2H, br m), 2.06-1.94 (3H, br m), 1.66-1.62 (2H, br m), 1.06 (9H, br m)
Reaction SMILES: CC1C=CC(C[S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=CC=1.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=1.CC[O-].[Na+].SCC(OCC)=O>C(O)C>[CH:24]([C:21]1[CH:22]=[CH:23][C:18]([CH2:17][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:19][CH:20]=1)([CH3:26])[CH3:25]
Reactant: CC(C)c1ccc(CBr)cc1
Reactant: CCOC(=O)CSCc1ccc(C)cc1
Agent: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCc1ccc(C(C)C)cc1

Procedure:
The procedure is as in Example 29 for the preparation of ethyl (4-methylbenzylthio)acetate, starting with 1-bromomethyl-4-isopropylbenzene (15 g), a 2M ethanolic solution of sodium ethylate (49 cc) and ethyl 2-mercaptoacetate (9.8 g) in ethanol (150 cc). Ethyl (4-isopropylbenzylthio)acetate (17.9 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][OH:6].[CH2:8]([C:15]([N:30]([CH3:32])[CH3:31])([CH2:28][CH3:29])[C:16]([C:18]1[CH:23]=[CH:22][C:21](OC)=[C:20]([O:26][CH3:27])[CH:19]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CC(N(C)C)=O>[CH2:8]([C:15]([N:30]([CH3:31])[CH3:32])([CH2:28][CH3:29])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:6][CH2:5][CH2:4][CH2:3][OH:7])=[C:20]([O:26][CH3:27])[CH:19]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(OC)c(OC)c1)N(C)C
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(OCCCO)c(OC)c1)N(C)C
Temperature: 120 °C
Reaction time: 18 h

Procedure:
0.40 mol of sodium hydride are suspended in 500 ml of dry dimethylacetamide and 72.3 ml (1.0 mol) of 1,3-propanediol are added dropwise at 0° C. Then 68.3 g (0.20 mol) of 2-benzyl-1-(3,4-dimethoxy-phenyl)-2-dimethylamino-butan-1-one in dimethylacetamide are added dropwise at 0° C. After the solution is stirred at 120° C. for 18 h, the solution is poured into water. The crude product is extracted with ethyl acetate, washed with water, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (40:60) as an eluent. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 0.69 (t, 3H), 1.83-1.92 (m, 1H), 2.04-2.16 (m, 3H), 2.38 (s, 6H), 2.40-2.55 (bs, 1H), 3.18-3.23 (m, 2H), 3.88 (s, 3H), 3.89 (t, 2H), 4.27 (t, 2H), 6.84 (d, 1H), 7.15-7.28 (m, 5H), 7.93 (d, 1H), 8.20 (dd, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:14][CH3:15])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:14][CH3:15])[C:11]([O:13][CH2:21][CH3:22])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCO
Reactant: CCC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(CC)c1ccc([N+](=O)[O-])cc1
Yield: 48 %

Procedure:
In 250 ml of ethanol was dissolved 16.71 g (0.08 mole) of 2-(4-nitrophenyl)-n-butyric acid and 15 ml of conc. sulfuric acid was then added and heated under reflux for 3.5 hours on an oil bath. After the ethanol was distilled off in vacuo, the residue was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution and dried over sodium sulfate. After the ethyl acetate was distilled off in vacuo, the residue was subjected to silica gel chromatography eluting with a mixture of benzene and n-hexane (1:1) to give 9.13 g (0.0385 mole, 48% yield) of ethyl 2-(4-nitrophenyl)-n-butyrate.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17]N(C)C=O>>[CH2:10]([N:9]([CH3:17])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(C)C=O
Reactant: c1ccc(CNc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CN(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
60% dispersion of sodium hydride in mineral oil (2.37 g, 0.0592 mol) was added to a solution of N-phenyl-N-benzylamine (10.33 g, 0.0564 mol) in anhydrous N,N-dimethylformamide (200 mL) at 0° C. The reaction mixture was warmed up to ambient temperature and stirred for 45 min. lodomethane (7.99 g, 0.0564 mol) was added dropwise and the stirring at ambient temperature was continued under an atmosphere of nitrogen for 20 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (250 mL) and water (200 mL). The organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (2:98) as mobile phase to yield N-benzyl-N-methyl-N-phenylamine (4.4 g, 0.0223 mol) as a yellow oil.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([N:19]=[C:20]=[S:21])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)([OH:4])(=[O:3])=[O:2].[Na:22].C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.C[N:37](C)CC=C>O>[S:1]([C:5]1[CH:6]=[C:7]([NH:19][C:20]([NH2:37])=[S:21])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15]([OH:18])(=[O:16])=[O:17])=[CH:10][CH:9]=2)([OH:4])(=[O:3])=[O:2].[Na:22]
Reactant: O=S(=O)(O)c1ccc2c(N=C=S)cc(S(=O)(=O)O)cc2c1
Reactant: C=CCN(C)C
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: [Na]
Solvent: O
Product: NC(=S)Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)ccc12
Temperature: 53 °C

Procedure:
Solid sodium 3,6-Disulfonapthylisothiocyanate (200 mg; 0.51 mmol) was added to a solution of poly-L-lysine (15-30 K) (50 mg) in a mixture of water (2 ml) and N,N-dimethyl-N-allylamine buffer (pH 9.5; 2ml). The resulting mixture was heated under nitrogen at 53° C. for 3 hours, when a ninhydrin test was negative. The cooled mixture was filtered and the filtrate concentrated to give a brownish solid residue. The solid residue was redissolved in water and passed through a column of Amberlite IR 120(Na) and then concentrated. The crude product was purified by gel filtration (Sephadex LH20; water) and freeze dried to give sodium 3,6-disulfonaphthylthiourea terminated poly-L-lysine BRI6047 as a white fluffy solid (87 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C@H:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:14]([CH:24]([CH3:26])[CH3:25])[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]=[C:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C@H:14]([CH:24]([CH3:26])[CH3:25])[CH2:13]1
Reactant: CC(C)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Oxalyl chloride (16 mL) dissolved in DCM (200 mL) was placed in a three-neck flask equipped with a stirrer and two addition funnels. One funnel contained DMSO (23 mL) in DCM (100 mL) and the other tert-butyl (2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidine-1-carboxylate (37 g) in DCM (100 mL). The contents of the flask were cooled to −78° C., and the DMSO solution was added dropwise. After 15 minutes, tert-butyl (2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidine-1-carboxylate was added. The reaction mixture was stirred for 30 minutes, and triethylamine (110 mL) was added. The cooling bath was removed, and water (100 mL) was added at room temperature and stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with DCM (3×100 mL). The combined organic layers were washed with brine (3×50 mL), dried over magnesium sulfate, filtered, and concentrated. The material was purified by silica gel chromatography (petroleum ether/ethyl acetate, 15/1) to afford tert-butyl (2S)-4-oxo-2-(propan-2-yl)pyrrolidine-1-carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:27]([C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1)[CH3:28]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Reactant: CCc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-ethylphenyl borate (0.40 g) and potassium carbonate (0.67 g) in toluene/ethanol/water (30/3/3 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.14 g), and the mixture was refluxed for 15 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate/hexane=1:1) to give pale yellow crystals of methyl 7-(4-ethylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (732 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:13][N:12]([CH3:18])[CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[ClH:19]>C(OCC)C>[Cl-:19].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:13][NH+:12]([CH3:18])[CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C23CCCC2CN(C)CC3)c1
Reactant: Cl
Solvent: CCOCC
Product: COc1cccc(C23CCCC2C[NH+](C)CC3)c1
Product: [Cl-]

Procedure:
A solution of 4a-(3-methoxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine in 100 ml. of diethyl ether was stirred while hydrogen chloride gas was bubbled through the solution. The reaction mixture was stirred for thirty minutes and then filtered. The solid product was recrystallized from diisopropyl ether and isopropanol to provide 4a-(3-methoxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindinium chloride. M.P. 175°-177° C.
Reaction SMILES: [ClH:1].[CH2:2]([NH2:5])[CH:3]=[CH2:4].C(N(C(C)C)CC)(C)C.[CH2:15]([O:22][C:23](=[O:26])[CH2:24]Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[ClH:1].[CH2:15]([O:22][C:23](=[O:26])[CH2:24][NH:5][CH2:2][CH:3]=[CH2:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CCN
Reactant: O=C(CBr)OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CCNCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To a solution of allylamine hydrochloride (5.0 g, 53.4 mmol) in tetrahydrofuran (100 mL) was added diisopropylethylamine (10 mL) and bromoacetic acid benzyl ester (3.06 g, 13.3 mmol) at 0° C. and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was added ethyl acetate and 1 N-hydrochloric acid solution, the organic layer was separated, and the aqueous layer was extracted two times with ethyl acetate. The organic layers were combined, washed with sodium thiosulfate solution and brine, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and to the obtained oil was added 4N-Hydrogen chloride in 1,4-Dioxane (3.5 mL). The mixture was concentrated under reduced pressure and lyophilized to give the title compound (2.12 g, 8.79 mmol, 66%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[C:13](N1C=CN=C1)([N:15]1C=CN=[CH:16]1)=O.Cl.CNC.C(N(C(C)C)CC)(C)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:15]([CH3:16])[CH3:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
A solution of 3-(4-bromophenyl)propionic acid (1.0 g, 4.37 mmol) in dichloromethane (30 ml) was treated in one portion with solid 1,1′-carbonyldiimidazole (707 mg, 4.36 mmol). This mixture was allowed to stir at room temperature for 15 minutes. Dimethylamine hydrochloride (360 mg, 4.42 mmol) was then added followed by diisopropylethylamine (0.76 ml, 4.4 mmol) and the stirring continued for 1 hour at room temperature. The reaction mixture was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a colourless oil (972 mg, 87%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:31](O)=[O:32])[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=2)=[C:11]([F:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:39][C:40](=[O:54])[NH:41][C:42]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)([CH3:38])([CH3:37])[CH3:36].CCN(C(C)C)C(C)C>ClCCl>[C:35]([O:39][C:40](=[O:54])[NH:41][C:42]1([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:43][CH2:44][N:45]([C:31]([C:17]2[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[F:34])[CH:16]=2)=[O:32])[CH2:46][CH2:47]1)([CH3:38])([CH3:36])[CH3:37]
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)O)c12
Reactant: CC(C)(C)OC(=O)NC1(c2ccccc2)CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)N3CCC(NC(=O)OC(C)(C)C)(c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 120 h
Yield: 15.9 %

Procedure:
A mixture of 6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (384 mg), (4-phenylpiperidin-4-yl)-carbamic acid tert-butyl ester (230 mg), DIPEA (427 μL) and BEP (456 mg) in dichloromethane (10 mL) was stirred at r.t. for 5 d. The solvent was distilled off in vacuo, the residue was re-dissolved in MTBE/ethyl acetate (v/v=1/1, 40 mL) and washed once with water, twice with saturated sodium bicarbonate solution, once with 1N sodium hydroxide solution and with brine. After evaporation of the solvents, the residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient) giving 95 mg (16%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:13])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:14])[CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH2:33][C:34]([NH:37][C:38](=[O:40])[CH3:39])([CH3:36])[CH3:35]>>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH:15]([C:3]1[C:4](=[O:14])[O:5][C:6]([CH3:13])([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:2]=1[OH:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:27]2[CH2:33][C:34]([NH:37][C:38](=[O:40])[CH3:39])([CH3:36])[CH3:35]
Reactant: CC1(c2ccccc2)OC(=O)C=C1O
Reactant: CC(=O)NC(C)(C)Cc1c[nH]c2ccc(Cl)cc12
Reactant: O=Cc1ccccc1
Product: CC(=O)NC(C)(C)Cc1c(C(C2=C(O)C(C)(c3ccccc3)OC2=O)c2ccccc2)[nH]c2ccc(Cl)cc12

Procedure:
Using general procedure D, rac-4-hydroxy-5-methyl-5-phenyl-5H-furan-2-one (prepared according to Example A3) was reacted with benzaldehyde and N-[2-(5-chloro-1H-indol-3-yl)-1,1-dimethyl-ethyl]-acetamide to give the title compound as pale brown solid. MS: 543.3 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][NH2:18].CCCCCC.CC(=O)OCC>S(Cl)(Cl)=O>[F:1][C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)=[O:6]
Reactant: NCc1cccs1
Reactant: O=C(O)c1ccc(F)nc1F
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(NCc1cccs1)c1ccc(F)nc1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
795 mg (5.0 mmol) of 2,6-difluoro-nicotinic acid were dissolved in thionyl chloride (15 ml) and the solution was heated for 2 h at 80° C. Concentration in vacuo was then carried out and the residue was taken up in dioxane (15 ml). 566 mg (5.0 mmol) of thiophen-2-yl-methanamine were then added and the mixture was stirred for 1 h at RT. Concentration in vacuo was then carried out and the residue was taken up in EA, washed with water, a sat. aq. Na2CO3 sol., water again and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 7:3) of the residue yielded 605 mg (2.4 mmol, 48%) of 2,6-difluoro-N-(thiophen-2-ylmethyl)nicotinamide.
Reaction SMILES: O.[BH4-].[Na+].[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C@@:12]2([CH3:37])[C:16](=[O:17])[N:15]([CH2:18][C:19]([O:21]CC3C=CC=CC=3)=[O:20])[C:14](=[O:29])[N:13]2[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:8][CH:7]=1)=[O:5]>C(O)C>[OH:5][CH2:4][C:6]1[CH:11]=[CH:10][C:9]([C@@:12]2([CH3:37])[C:16](=[O:17])[N:15]([CH2:18][C:19]([OH:21])=[O:20])[C:14](=[O:29])[N:13]2[CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:8][CH:7]=1
Reactant: C[C@]1(c2ccc(C=O)cc2)C(=O)N(CC(=O)OCc2ccccc2)C(=O)N1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@]1(c2ccc(CO)cc2)C(=O)N(CC(=O)O)C(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
20 ml of water and then, at 0° C., 22 mg (0.6 mmol) of sodium borohydride were added to a solution of 500 mg (1.1 mmol) of 8.2 in 50 ml of ethanol. After stirring at 0° C. for 40 min, the reaction mixture was concentrated in vacuo, the residue was heated at 50° C. for 12 h in 30 ml of 6 N hydrochloric acid/THF (1:1) and the reaction mixture was allowed to stand overnight at room temperature. The mixture was extracted with dichloromethane and the organic phase was dried over sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was treated with water and freeze-dried. 440 mg of crude 8.3 were obtained, which was employed in the next synthesis step without further purification.